rTMS + Virtual Reality Therapy for Mild Cognitive Impairment

(rTMS+iVCT Trial)

Overseen By Lasi McGhee

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Central Arkansas Veterans Healthcare System

Must not be taking: Seizure medications, Ototoxic medications

Disqualifiers: Seizures, Stroke, Bipolar, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 14

Duration: 2 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This clinical trial is being conducted to see if brain stimulation and brain training together improves cognitive functioning and mood in older adults diagnosed with Mild Cognitive Impairment (MCI). Brain stimulation will be done using repetitive Transcranial Magnetic Stimulation (rTMS). Brain training will be done using immersive virtual reality cognitive training (iVCT) program. The goals of this clinical trail are as follows: * Examine if rTMS+iVCT intervention can improve and sustain objective cognitive functioning in individuals with MCI more than control or rTMS only groups * Examine if rTMS+iVCT intervention improves participants mental health symptoms, functional abilities, and quality of life more than control or rTMS only groups * Examine the impact of rTMS+iVCT intervention on caregiver burden. Eligible participants will be assigned to a standard treatment (no intervention control) group, rTMS only group of rTMS+iVCT group. All participants will undergo baseline assessment to evaluate their cognitive, emotional, and functional abilities. Those in the rTMS only group will receive rTMS treatments for five days per week for two weeks (total of ten sessions). Those in the rTMS+iVCT group will receive rTMS treatment followed by iVCT training for five days a week for two weeks (total of ten sessions). All participants will then repeat testing 2 weeks and three months after baseline testing to assess for possible treatment related changes and lasting effects.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications known to increase the risk of seizures and ototoxic medications (medications that can damage the ear). If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the treatment rTMS + Virtual Reality Therapy for Mild Cognitive Impairment?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can improve cognitive function in people with mild cognitive impairment (MCI) and early Alzheimer's disease. Studies found that rTMS increased cognitive scores and brain activity in areas related to thinking and memory, suggesting it may help slow cognitive decline. ^{1 2 3 4 5}

Is rTMS safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for humans, with guidelines established to minimize risks. Some mild adverse effects have been reported, but serious side effects like seizures are rare and usually occur when safety guidelines are not followed. ^{1 6 7 8 9}

How does the treatment rTMS + Virtual Reality Therapy for Mild Cognitive Impairment differ from other treatments?

The treatment combines repetitive transcranial magnetic stimulation (rTMS), which uses magnetic fields to stimulate brain activity, with virtual reality therapy, offering a unique approach that targets cognitive function through both brain stimulation and immersive experiences. This combination is novel compared to standard treatments, as it aims to enhance cognitive improvement by engaging multiple brain areas and providing a more interactive therapeutic experience. ^{1 3 10 11 12}

Eligibility Criteria

This trial is for adults over 55 with Mild Cognitive Impairment (MCI) who score at least 18 on the MoCA test. It's not suitable for those with implanted devices, under 55, seizure risks, history of certain neurological issues, or sensitivity to light and sound.

Inclusion Criteria

I am 55 years old or older.

You have previously been diagnosed with Mild Cognitive Impairment.

My mental function score is 18 or higher.

Exclusion Criteria

I or my close family members have had seizures.

You have a history of Tourette's syndrome or currently experience uncontrollable body movements.

I have had a stroke, aneurysm, or brain surgery in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants undergo baseline assessment to evaluate cognitive, emotional, and functional abilities

1 week

1 visit (in-person)

Treatment

Participants receive rTMS or rTMS+iVCT treatment for 5 days a week for 2 weeks

2 weeks

10 visits (in-person)

Post-treatment Assessment

Participants repeat testing to assess treatment-related changes

2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

1 visit (in-person)

Treatment Details

Interventions

• iVCT
• rTMS

Trial Overview The study tests if brain stimulation (rTMS) combined with virtual reality cognitive training (iVCT) can improve cognition and mood in MCI patients more effectively than rTMS alone or no treatment.

Participant Groups

Group I: rTMS+iVCT Experimental Treatment 1 Intervention

This group will be randomized to receive rTMS and iVCT treatment

Group II: rTMS Active Control 1 Intervention

This group will be randomized to receive rTMS treatment

Group III: Standard Treatment Active Control 1 Intervention

This arm will be followed without intervention

rTMS is already approved in United States, European Union for the following indications:

Approved in United States as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder
• Migraines
• Smoking cessation

Approved in European Union as rTMS for:

• Obsessive-Compulsive Disorder (OCD)
• Major Depressive Disorder

Who Is Running the Clinical Trial?

Central Arkansas Veterans Healthcare System

Lead Sponsor

Trials

24

Recruited

343,000+

Findings from Research

High-frequency repetitive transcranial magnetic stimulation (HFrTMS) showed significant short-term improvements in general cognition for patients with Alzheimer's disease (AD), while anodal transcranial direct current stimulation (atDCS) also had positive effects, but to a lesser extent.

Cognitive training during rTMS or tDCS may negatively impact general cognition, and the best responses to these treatments were observed in patients with AD rather than those with mild cognitive impairment (MCI).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer's disease and mild cognitive impairment: a component network meta-analysis. Chu, CS., Li, CT., Brunoni, AR., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) significantly improves cognitive function in patients with mild cognitive impairment (MCI) and early Alzheimer's Disease (AD), with a mean effect size of 1.17 based on a meta-analysis of 12 studies involving 438 participants.

The most effective rTMS protocol involved 10 Hz frequency and stimulation of the dorsolateral prefrontal cortex (DLPFC) for 20 sessions, showing lasting cognitive benefits for up to one month after treatment, particularly for patients with MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive Enhancement of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment and Early Alzheimer's Disease: A Systematic Review and Meta-Analysis. Xie, Y., Li, Y., Nie, L., et al.[2021]

In a double-blind, sham-controlled trial involving 24 patients with amnestic mild cognitive impairment (aMCI), high-frequency repetitive transcranial magnetic stimulation (rTMS) significantly improved cognitive function as measured by the Montreal Cognitive Assessment after 4 weeks of treatment.

The rTMS treatment also led to notable changes in brain activity, specifically increasing the amplitude of low-frequency fluctuations in key cognitive areas, suggesting that rTMS may enhance cognitive function by altering brain activity patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial. Yuan, LQ., Zeng, Q., Wang, D., et al.[2021]

In a study of 30 patients with mild to moderate Alzheimer's disease, those receiving real rTMS combined with cognitive training showed significant improvements in cognitive function and behavior compared to a sham treatment group after 4 weeks.

The study found that the N-acetylaspartate/creatine (NAA/Cr) ratio in the left dorsolateral prefrontal cortex (DLPFC) increased significantly in the real rTMS group, suggesting potential neuronal benefits associated with improved cognitive outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease. Zhang, F., Qin, Y., Xie, L., et al.[2020]

In a preliminary study involving 27 patients with mild cognitive impairment (MCI), high-frequency rTMS applied to the dorsolateral prefrontal cortex significantly improved cognitive functions, specifically semantic fluency and visuo-spatial performance, compared to a sham group.

The study also found that rTMS led to increased functional connectivity in brain networks associated with executive functions, suggesting a potential mechanism for counteracting cognitive decline in MCI, although no significant changes in regional brain atrophy were observed over six months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation (rTMS) of Dorsolateral Prefrontal Cortex May Influence Semantic Fluency and Functional Connectivity in Fronto-Parietal Network in Mild Cognitive Impairment (MCI). Esposito, S., Trojsi, F., Cirillo, G., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

Repetitive transcranial magnetic stimulation (rTMS) may significantly improve global cognitive function and memory in patients with mild cognitive impairment (MCI), based on a meta-analysis of nine studies involving 369 patients.

While rTMS shows promise for cognitive enhancement, it is associated with a higher rate of mild adverse effects compared to control groups, indicating that while generally safe, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Improving Cognitive Function in Patients With Mild Cognitive Impairment: A Systematic Review. Jiang, L., Cui, H., Zhang, C., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) can effectively improve cognitive function and behavioral symptoms in dementia patients, as demonstrated in a case where a patient showed significant improvement after switching from 1 Hz to 10 Hz rTMS.

While rTMS is generally beneficial, it can lead to adverse reactions such as seizures; however, adjusting the treatment parameters (like reducing the frequency) can help mitigate these risks and continue to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The repetitive transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia: a case report. Yang, Z., Zhou, Y.[2023]

In a study involving 40 patients with mild cognitive impairment (MCI), 10 sessions of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex significantly improved memory performance compared to a sham treatment.

The improvement in memory was linked to changes in brain activity and connectivity, specifically increased activity in certain brain regions and altered functional connectivity, suggesting that rTMS may enhance memory by modulating neuronal networks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Frequency rTMS Could Improve Impaired Memory in Mild Cognitive Impairment Patients in China: A Randomized Controlled Study. Wang, T., Guo, Z., Wu, H., et al.[2023]

In a pilot study involving 30 Alzheimer's disease patients, focal repetitive transcranial magnetic stimulation (rTMS) using the H2-coil showed a trend toward improved cognitive function, with a mean decrease of -1.01 points on the ADAS-Cog scale after treatment, although this effect was not sustained two months post-treatment.

The study indicates that rTMS with the H2-coil is safe and feasible for Alzheimer's patients, suggesting potential cognitive benefits that warrant further investigation in larger trials, especially when combined with cognitive rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study. Leocani, L., Dalla Costa, G., Coppi, E., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive brain stimulation technique that can enhance brain excitability and potentially improve conditions like stroke, Parkinson's disease, and depression, as discussed in a 2010 symposium with insights from both animal studies and small clinical trials.

While there is significant interest and some signs of therapeutic success with rTMS, the current models explaining its effects may need refinement to fully understand the underlying mechanisms and outcomes observed in various studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain stimulation and brain repair--rTMS: from animal experiment to clinical trials--what do we know? Platz, T., Rothwell, JC.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer's disease and mild cognitive impairment: a component network meta-analysis. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Cognitive Enhancement of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment and Early Alzheimer's Disease: A Systematic Review and Meta-Analysis. [2021]

3. India pubmed.ncbi.nlm.nih.gov

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial. [2021]

4. Austria pubmed.ncbi.nlm.nih.gov

High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer's disease. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation (rTMS) of Dorsolateral Prefrontal Cortex May Influence Semantic Fluency and Functional Connectivity in Fronto-Parietal Network in Mild Cognitive Impairment (MCI). [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Improving Cognitive Function in Patients With Mild Cognitive Impairment: A Systematic Review. [2021]

9. England pubmed.ncbi.nlm.nih.gov

The repetitive transcranial magnetic stimulation in Alzheimer's disease patients with behavioral and psychological symptoms of dementia: a case report. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

High-Frequency rTMS Could Improve Impaired Memory in Mild Cognitive Impairment Patients in China: A Randomized Controlled Study. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study. [2021]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Brain stimulation and brain repair--rTMS: from animal experiment to clinical trials--what do we know? [2013]